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A Dominant Negative Human Peroxisome Proliferator-Activated Receptor (PPAR) Is a Constitutive Transcriptional Corepressor and Inhibits Signaling through All PPAR Isoforms

Departments of Clinical Biochemistry (R.K.S., A.J.V.-P., S.O.) and Medicine (M.G., V.K.K.C., S.O.), University of Cambridge, Addenbrooke’s Hospital, Cambridge CB2 2QQ, United Kingdom; Institut National de la Santé et de la Recherche Médicale U.508 (A.M.), Institut Pasteur de Lille, 59019 Lille Cedex, France; Metabolic Research Laboratory (D.W., G.F.G.), Oxford Centre for Diabetes, Endocrinology and Metabolism, Nuffield Department of Clinical Medicine, University of Oxford, Churchill Hospital, Oxford OX3 7LJ, United Kingdom; MRC-Laboratory of Molecular Biology (J.W.R.S.), Cambridge CB2 2QH, United Kingdom

Address all correspondence and requests for reprints to: Robert Semple, Department of Clinical Biochemistry, Addenbrooke’s Hospital, Cambridge CB2 2QR, United Kingdom. E-mail: rks16{at}cam.ac.uk.

Several missense mutations in the ligand-binding domain of human peroxisome proliferator-activated receptor (PPAR) have been described in subjects with dominantly inherited severe insulin resistance associated with partial lipodystrophy, hypertension, and dyslipidemia. These mutant receptors behave as dominant-negative inhibitors of PPAR signaling when studied in transfected cells. The extent to which such dominant-negative effects extend to signaling through other coexpressed PPAR isoforms has not been evaluated. To examine these issues further, we have created a PPAR mutant harboring twin substitutions, Leu459Ala and Glu462Ala, within the ligand binding domain (PPAR_mut), examined its signaling properties, and compared the effects of dominant-negative PPAR and PPAR mutants on basal and ligand-induced gene transcription in adipocytes and hepatocytes. PPAR_mut was transcriptionally inactive, repressed basal activity from a PPAR response element-containing promoter, inhibited the coactivator function of cotransfected PPAR- coactivator 1, and strongly inhibited the transcriptional response to cotransfected wild-type receptor. In contrast to PPAR, wild-type PPAR failed to recruit the transcriptional corepressors NCoR and SMRT. However, PPAR_mut avidly recruited these corepressors in a ligand-dissociable manner. In hepatocytes and adipocytes, both PPAR_mut and the corresponding PPAR mutant were capable of inhibiting the expression of genes primarily regulated by PPAR, -, or - ligands, albeit with some differences in potency. Thus, dominant-negative forms of PPAR and PPAR are capable of interfering with PPAR signaling in a manner that is not wholly restricted to their cognate target genes. These findings may have implications for the pathogenesis of human syndromes resulting from mutations in this family of transcription factors.

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